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Extracellular mediators in atherosclerosis and thrombosis: lessons from thrombin receptor knockout mice
Christopher D Major1, Rosemary J Santulli, Claudia K Derian
1Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Spring House, PA 19477-0776, USA.
Abstract:
It is well appreciated that thrombin as well as other proteases can act as signaling molecules that specifically regulate cells by cleaving and activating members of a novel class of protease-activated receptors (PARs). The utility of gene knockout strategies to define and better comprehend the physiological role of specific proteins is perhaps best exemplified in the field of thrombin receptors. The development of PAR knockout mice has provided the unique opportunity to identify and characterize new members of this novel family of GPCRs, evaluate the interaction of PARs jointly expressed in common cells and tissues, and better understand the role of PARs in thrombosis, restenosis, vascular remodeling, angiogenesis, and inflammation. Presently, 4 members of the PAR family have been cloned and identified. In this review, we examine experimental evidence gleaned from PAR-/- mouse models as well as how the use of PAR-/- mice has provided insights toward understanding the physiological role of thrombin in cells of the vascular system and vascular pathology.
Insights
Protease-activated receptors (PARs) are crucial signaling molecules. PAR knockout mice reveal their vital roles in vascular system functions and diseases like thrombosis and inflammation.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Proteases, such as thrombin, function as signaling molecules by activating protease-activated receptors (PARs).
- PARs represent a novel class of G protein-coupled receptors (GPCRs) involved in cellular regulation.
- Understanding the physiological roles of PARs is critical for various biological processes.
Purpose of the Study:
- To review the insights gained from using PAR knockout mouse models.
- To elucidate the physiological functions of PARs in the vascular system.
- To explore the involvement of PARs in vascular pathologies.
Main Methods:
- Utilizing gene knockout strategies to generate PAR-deficient (PAR-/-) mice.
- Analyzing experimental evidence from PAR-/- mouse models.
- Characterizing novel PAR family members and their interactions.
Main Results:
- PAR-/- mice have been instrumental in identifying and characterizing new PAR family members.
- These models allow for the evaluation of interactions between co-expressed PARs.
- Insights into the role of PARs in thrombosis, restenosis, vascular remodeling, angiogenesis, and inflammation have been gained.
Conclusions:
- PAR knockout mouse models are essential tools for understanding PAR function.
- PARs play significant roles in the vascular system and associated pathologies.
- Further research using these models will continue to advance our knowledge of thrombin signaling.